JP2505268B2 - Recombinant DNA expression vector - Google Patents
Recombinant DNA expression vectorInfo
- Publication number
- JP2505268B2 JP2505268B2 JP63506088A JP50608888A JP2505268B2 JP 2505268 B2 JP2505268 B2 JP 2505268B2 JP 63506088 A JP63506088 A JP 63506088A JP 50608888 A JP50608888 A JP 50608888A JP 2505268 B2 JP2505268 B2 JP 2505268B2
- Authority
- JP
- Japan
- Prior art keywords
- hcmv
- gene
- mie
- dna
- heterologous gene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000013604 expression vector Substances 0.000 title abstract description 6
- 108020004511 Recombinant DNA Proteins 0.000 title description 3
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 55
- 239000013598 vector Substances 0.000 claims abstract description 27
- 108091026890 Coding region Proteins 0.000 claims abstract description 17
- 239000003623 enhancer Substances 0.000 claims abstract description 17
- 108091026898 Leader sequence (mRNA) Proteins 0.000 claims abstract description 14
- 229920001184 polypeptide Polymers 0.000 claims abstract description 13
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 13
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 13
- 108020004414 DNA Proteins 0.000 claims abstract description 12
- 230000014509 gene expression Effects 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 3
- 239000013612 plasmid Substances 0.000 claims description 15
- 230000014621 translational initiation Effects 0.000 claims description 15
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 14
- 102000005396 glutamine synthetase Human genes 0.000 claims description 10
- 108020002326 glutamine synthetase Proteins 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 238000011144 upstream manufacturing Methods 0.000 claims description 4
- 108010065825 Immunoglobulin Light Chains Proteins 0.000 claims description 3
- 238000012258 culturing Methods 0.000 claims description 3
- 230000008488 polyadenylation Effects 0.000 claims description 3
- 102000013463 Immunoglobulin Light Chains Human genes 0.000 claims description 2
- 238000003780 insertion Methods 0.000 claims description 2
- 230000037431 insertion Effects 0.000 claims description 2
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- 102000005876 Tissue Inhibitor of Metalloproteinases Human genes 0.000 claims 2
- 108700026220 vif Genes Proteins 0.000 claims 1
- 241000701024 Human betaherpesvirus 5 Species 0.000 abstract description 4
- 108700002232 Immediate-Early Genes Proteins 0.000 abstract description 4
- 210000004027 cell Anatomy 0.000 description 34
- SXTAYKAGBXMACB-UHFFFAOYSA-N methionine sulfoximine Chemical compound CS(=N)(=O)CCC(N)C(O)=O SXTAYKAGBXMACB-UHFFFAOYSA-N 0.000 description 14
- 239000012634 fragment Substances 0.000 description 13
- 238000013519 translation Methods 0.000 description 11
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- 102000004169 proteins and genes Human genes 0.000 description 6
- 238000013518 transcription Methods 0.000 description 6
- 230000035897 transcription Effects 0.000 description 6
- 238000001890 transfection Methods 0.000 description 6
- 230000028327 secretion Effects 0.000 description 5
- 108091034117 Oligonucleotide Proteins 0.000 description 4
- 108091023045 Untranslated Region Proteins 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
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- 101100148606 Caenorhabditis elegans pst-1 gene Proteins 0.000 description 3
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- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
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- 102000018358 immunoglobulin Human genes 0.000 description 2
- 229940072221 immunoglobulins Drugs 0.000 description 2
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- 238000012360 testing method Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 1
- 108090000746 Chymosin Proteins 0.000 description 1
- 101100007328 Cocos nucifera COS-1 gene Proteins 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- 108010054576 Deoxyribonuclease EcoRI Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102100031416 Gastric triacylglycerol lipase Human genes 0.000 description 1
- 102000018997 Growth Hormone Human genes 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- 102000008072 Lymphokines Human genes 0.000 description 1
- 108010074338 Lymphokines Proteins 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 108091006088 activator proteins Proteins 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229940080701 chymosin Drugs 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 108010091264 gastric triacylglycerol lipase Proteins 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940065638 intron a Drugs 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- GNOLWGAJQVLBSM-UHFFFAOYSA-N n,n,5,7-tetramethyl-1,2,3,4-tetrahydronaphthalen-1-amine Chemical compound C1=C(C)C=C2C(N(C)C)CCCC2=C1C GNOLWGAJQVLBSM-UHFFFAOYSA-N 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 108010073863 saruplase Proteins 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 238000003151 transfection method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
- C07K14/8146—Metalloprotease (E.C. 3.4.24) inhibitors, e.g. tissue inhibitor of metallo proteinase, TIMP
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6456—Plasminogen activators
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/93—Ligases (6)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/16011—Herpesviridae
- C12N2710/16111—Cytomegalovirus, e.g. human herpesvirus 5
- C12N2710/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2830/00—Vector systems having a special element relevant for transcription
- C12N2830/42—Vector systems having a special element relevant for transcription being an intron or intervening sequence for splicing and/or stability of RNA
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Biotechnology (AREA)
- Biophysics (AREA)
- Microbiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Virology (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Enzymes And Modification Thereof (AREA)
- Detection And Correction Of Errors (AREA)
- Peptides Or Proteins (AREA)
- Measurement And Recording Of Electrical Phenomena And Electrical Characteristics Of The Living Body (AREA)
Abstract
The invention provides expression vectors containing the promoter, enhancer and substantially complete 5'-untranslated region including the first intron of the major immediate early gene of human cytomegalovirus. Further vectors including the hCMV-MIE DNA linked directly to the coding sequence of a heterologous gene are described, Host cells transfected with the vectors and a process for producing heterologous polypeptides using the vectors and the use of the hCMV-MIE DNA for expression of a heterologous gene are also included within the invention.
Description
【発明の詳細な説明】 発明の分野 本発明は、ヒトサイトメガロウイルス主要前初期遺伝
子からのDNA配列を含有する発現ベクター、このベクタ
ーを含有する宿主細胞、上記配列を含有するベクターを
用いて所望のポリペプチドを製造する方法、および上記
DNA配列の使用に関する。FIELD OF THE INVENTION The present invention is directed to expression vectors containing a DNA sequence from the human immediate-megalovirus major immediate early gene, host cells containing this vector, and vectors containing the above sequences. And a method for producing the polypeptide of
Regarding the use of DNA sequences.
発明の背景 組換えDNA技術の分野における研究者の主たる目的
は、特定のポリペプチドの可能な限り高レベルの製造を
達成することである。これは、天然にはあまり豊富でな
いポリペプチドを製造するために組換えDNA技術の活用
を願つている営利機構においてはとくに真実である。BACKGROUND OF THE INVENTION The main purpose of researchers in the field of recombinant DNA technology is to achieve the highest possible level of production of a particular polypeptide. This is especially true in commercial organizations that desire the use of recombinant DNA technology to produce polypeptides that are less abundant in nature.
一般的にDNA技術の応用は、所望のポリペプチドをコ
ードする遺伝子のクローニング、クローン化された遺伝
子の適当な発現ベクター中への配置、このベクターによ
る宿主細胞系のトランスフエクシヨン、およびトランス
フエクシヨンを受けた細胞系の培養によるポリペプチド
の製造が包含される。ある特定のベクターもしくは細胞
系またはそれらの組合せが有用なレベルの産生を導くか
どうかを予測することはほとんど不可能である。Generally, applications of DNA technology include cloning of the gene encoding the desired polypeptide, placement of the cloned gene in an appropriate expression vector, transfer vector of the host cell line by this vector, and transfection. Production of the polypeptide by culturing the cell line which has undergone the treatment. It is almost impossible to predict whether a particular vector or cell line or combination thereof will lead to useful levels of production.
一般に、トランスフエクシヨンを受けた細胞系によつ
て産生されるポリペプチドの量に有意に影響する因子
は、１）遺伝子コピー数、２）遺伝子の転写およびmRNA
の翻訳の効率、３）mRNAの安定性、ならびに４）タンパ
ク質の分泌効率である。In general, the factors that significantly affect the amount of polypeptide produced by a cell line that has undergone transfer are: 1) gene copy number, 2) gene transcription and mRNA.
Translation efficiency, 3) mRNA stability, and 4) protein secretion efficiency.
組換えポリペプチドの発現レベルの増大を目指す大部
分の研究は、転写開始機構の改良に集中されてきた。そ
の結果、効率的な翻訳に影響する因子の理解および解明
ははるかに遅れていて、ある特定のDNA配列が効率的な
翻訳を達成するのに有用であるかを予測することは不可
能である。Most research aimed at increasing the expression level of recombinant polypeptides has focused on improving the transcription initiation machinery. As a result, understanding and elucidation of the factors that affect efficient translation is far behind, and it is impossible to predict whether a particular DNA sequence will be useful in achieving efficient translation. .
翻訳を研究する試みは、大部分、コンセンサス翻訳開
始シグナルの周囲のDNA配列が翻訳開始にどのような影
響をもつかを決定するために、これを変化させるもので
ある〔コザク（Kozak,M.）：セル、第41巻、第283〜292
頁、1986年〕。Most attempts to study translation alter this to determine how the DNA sequence surrounding the consensus translation initiation signal affects translation initiation [Kozak, M. ): Cell, Volume 41, 283-292
Page, 1986].
所望の異種遺伝子の発現が関与する研究では通常、異
種遺伝子の暗号配列と少なくとも一部の５′非翻訳配列
の両者を、翻訳開始が遺伝子の天然配列に由来するよう
に使用している。このアプローチは、多分、５′非翻訳
領域の「ハイブリツド法」の結果として、また、特定の
５−非翻訳配列の存在は翻訳開始の劣化を招くという事
実から、当てにならないことが明らかにされた〔コザク
（Kozak,M.）：プロシーデイング・オブ・ザ・ナシヨナ
ル・アカデミー・オブ・サイエンシズ、第83巻、第2850
〜2854頁、1986年；およびペレチア（Pelletier）およ
びゾネンベルク（Sonenberg）：セル、第40巻、第515〜
526頁、1985年〕。翻訳におけるこの変化は産生する生
成物の量に有害な効果を与える。Studies involving the expression of the desired heterologous gene typically use both the coding sequence of the heterologous gene and at least a portion of the 5'untranslated sequences such that the translation initiation is derived from the native sequence of the gene. This approach proved to be unreliable, presumably as a result of the "hybridization" of the 5'untranslated region and due to the fact that the presence of certain 5-untranslated sequences leads to deterioration of translation initiation. Kozak, M .: Proceeding of the National Academy of Sciences, Volume 83, 2850
~ 2854, 1986; and Pelletier and Sonenberg: Cell, Volume 40, 515-.
526, 1985]. This change in translation has a deleterious effect on the amount of product produced.
以前の研究〔ボシヤート（Boshart）ら：セル、第41
巻、第521〜530頁、1985年、およびパスロー（Paslea
u）ら：ジーン、第38頁、第227〜232頁、1985年；ステ
ンベルグら：ジヤーナル・オブ・ヴアイロロジー、第48
巻、第１号、第190〜199頁、1984年；トムセンら：プロ
シーデイングズ・オブ・ナシヨナル・アカデミー・オブ
・サイエンシズ・オブ・サ・ユナイテツド・ステイツ・
オブ・アメリカ、第81巻、第659〜663頁、1984年；なら
びにフエツキング（Foecking）およびホフステツター
（Hofstetter）：ジーン、第45巻、第101〜105頁、1986
年〕では、発現ベクター中にhCMV-MIE遺伝子の上流領域
からの配列が使用されていた。しかしながら、これら
は、もつぱら、プロモーターおよび／またはエンハンサ
ーとしての配列の使用に関するものであつた。スペーテ
（Spaete）およびモカルスキー（ジヤーナル・オブ・ヴ
アイロロジー、第56巻、第１号、第135〜143頁、1985
年）は、異種遺伝子の発現のためのプロモーターとし
て、プロモーター、エンハンンサーおよび一部の５′−
非翻訳領域を包含するhCMV-MIE遺伝子のPst1〜Pst1フラ
グメントを使用している。翻訳を達成するために、異種
遺伝子の天然の５′−非翻訳領域が使用された。Previous work [Boshart et al .: Cell, No. 41
Volume 521-530, 1985, and Paslea (Paslea
u) et al .: Jean, pp. 38, 227-232, 1985; Stenberg et al .: Journal of Virology, pp. 48.
Volume 1, Issue 190-199, 1984; Thomsen et al .: Proceedings of National Academy of Sciences of the United States.
Of America, 81, 659-663, 1984; and Foecking and Hofstetter: Jean, 45, 101-105, 1986.
[Year], a sequence from the upstream region of the hCMV-MIE gene was used in the expression vector. However, these have involved the use of sequences as glutinae, promoters and / or enhancers. Spaete and Mokarsky (Journal of Virology, Vol. 56, No. 1, pp. 135-143, 1985)
As a promoter for the expression of heterologous genes, promoters, enhancers and some 5'-
The Pst1 to Pst1 fragment of the hCMV-MIE gene encompassing the untranslated region is used. To achieve translation, the natural 5'-untranslated region of the heterologous gene was used.
公告されたヨーロツパ特許出願第260148号には、異種
タンパク質の連続的製造方法が記載されている。構築さ
れた発現ベクターは、安定化配列として、hCMV-MIE遺伝
子の５′−非翻訳領域の一部を包含する。安定化配列は
所望の異種タンパク質をコードする遺伝子の５′−非翻
訳領域中に置かれる。すなわち、この場合も、遺伝子の
天然５′−非翻訳領域が翻訳に必須であることが教示さ
れている。Published European patent application No. 260148 describes a continuous process for the production of heterologous proteins. The constructed expression vector contains a part of the 5'-untranslated region of the hCMV-MIE gene as a stabilizing sequence. The stabilizing sequence is placed in the 5'-untranslated region of the gene encoding the desired heterologous protein. That is, in this case as well, it is taught that the natural 5'-untranslated region of the gene is essential for translation.
発明の要約 第一の特徴として本発明はヒトサイトメガロウイルス
の主要前初期遺伝子のプロモーター、エンハンサー、お
よび最初のイントロンを含めて実質的に完全な５′−非
翻訳領域からなるDNA配列を含有するベクターを提供す
る。SUMMARY OF THE INVENTION In a first aspect, the invention comprises a DNA sequence consisting of a substantially complete 5'-untranslated region including the promoter, enhancer, and first intron of the major immediate early gene of human cytomegalovirus. Provide the vector.
本発明の第一の特徴の好ましい態様においては、ベク
ターは異種遺伝子の挿入のための制限部位を含有する。In a preferred embodiment of the first aspect of the invention, the vector contains restriction sites for insertion of heterologous genes.
本発明は、ヒトサイトメガロウイルスの主要前初期遺
伝子（hCMV-MIE）のプロモーター、エンハンサーおよび
完全５′−非翻訳領域からなるDNA配列を異種遺伝子の
上流に含有するベクターが異種遺伝子生成物の高レベル
の発現を生じることの発見に基づくものである。とく
に、hCMV-MIEから誘導されたDNAを異種遺伝子の暗号配
列に直接連結すると高レベルのmRNA翻訳が達成すること
の発見は全く予期し得ないものであつた。このmRNAの効
率的な翻訳は一貫して達成され、発現される特定の異種
遺伝子に依存するものではないようである。The present invention provides a vector containing a DNA sequence consisting of the promoter, enhancer and complete 5'-untranslated region of the major immediate early gene (hCMV-MIE) of human cytomegalovirus upstream of a heterologous gene to enhance the production of a heterologous gene product. It is based on the finding that it produces a level of expression. In particular, the finding that direct ligation of hCMV-MIE-derived DNA to the coding sequences of heterologous genes achieves high levels of mRNA translation was completely unexpected. Efficient translation of this mRNA is consistently achieved and does not appear to depend on the particular heterologous gene expressed.
本発明は、第二の特徴として、ヒトサイトメガロウイ
ルスの主要初期遺伝子のプロモーター、エンハンサー、
および最初のイントロンを含めて実質的に完全な５′−
非翻訳領域からなるDNA配列を異種遺伝子の上流に含有
するベクターを提供する。The present invention has, as a second feature, promoters, enhancers of major early genes of human cytomegalovirus,
And a substantially complete 5'-, including the first intron
A vector containing a DNA sequence consisting of an untranslated region upstream of a heterologous gene is provided.
本発明の第二の特徴によるhCMV-MIE誘導DNAは、たと
えば異種遺伝子の５′−非翻訳領域のような介在配列に
よつて異種遺伝子の暗号配列から分離されていてもよ
い。hCMV-MIE誘導DNAは異種遺伝子の暗号配列に直接連
結するのが有利である。The hCMV-MIE-derived DNA according to the second aspect of the invention may be separated from the coding sequence of the heterologous gene by an intervening sequence such as the 5'-untranslated region of the heterologous gene. Advantageously, the hCMV-MIE-derived DNA is directly linked to the coding sequence of a heterologous gene.
本発明の第二の特徴の好ましい態様においては、本発
明は、hCMV-MIE遺伝子のプロモーター、エンハンサー、
および最初のイントロンを含めて実質的に完全な５′−
非翻訳領域に、異種遺伝子のDNA暗号配列が直接連絡し
てなるDNA配列を含有するベクターを提供する。In a preferred embodiment of the second aspect of the present invention, the present invention provides a hCMV-MIE gene promoter, enhancer,
And a substantially complete 5'-, including the first intron
Provided is a vector containing a DNA sequence in which the DNA coding sequence of a heterologous gene is directly linked to the untranslated region.
hCMV-MIE誘導配列は、天然のhCMV-MIE翻訳開始シグナ
ルと同一の配列を包含することが好ましい。しかしなが
ら、所望のポリペプチドの暗号配列への連結を容易にす
るため、すなわち便利な制限酵素認識部位を導入するこ
とにより、天然の翻訳開始シグナルを修飾することが必
要であるかまたは有利である。たとえば、翻訳開始部位
はNcoI認識部位を与えるように修飾するのが有利であ
る。The hCMV-MIE inducible sequence preferably includes a sequence identical to the native hCMV-MIE translation initiation signal. However, it is necessary or advantageous to modify the natural translation initiation signal to facilitate ligation of the desired polypeptide to the coding sequence, ie by introducing convenient restriction enzyme recognition sites. For example, the translation initiation site is advantageously modified to provide an NcoI recognition site.
異種遺伝子は、真核生物ポリペプチド、たとえば、酵
素たとえばキモシンもしくは胃リパーゼ；酵素インヒビ
ターたとえばメタロプロテナーゼの組織インヒビター
（TIMP）；ホルモンたとえば成長ホルモン；リンホカイ
ンたとえばインターフエロン；プラスミノーゲンアクテ
イベーターたとえば組織プラスミノーゲンアクテイベー
ター（tPA）もしくはプロウロキナーゼのような哺乳動
物ポリペプチド；または抗体−酵素もしくは抗体−トキ
シンキメラのような二元的活性を有するキメラ免疫グロ
ブリンを包含する天然、修飾もしくはキメラ免疫グロブ
リンもしくはそのフラグメントをコードする遺伝子とす
ることができる。Heterologous genes include eukaryotic polypeptides such as enzymes such as chymosin or gastric lipase; enzyme inhibitors such as tissue inhibitors of metalloproteinases (TIMP); hormones such as growth hormone; lymphokines such as interferons; plasminogen activators such as tissue plus. Mammalian polypeptides such as minogen activator (tPA) or prourokinase; or natural, modified or chimeric immunoglobulins, including chimeric immunoglobulins with dual activity such as antibody-enzyme or antibody-toxin chimera or It can be a gene encoding the fragment.
本発明の第三の特徴によれば、本発明は、本発明の第
一または第二の特徴によるベクターでトランスフエクシ
ヨンされた宿主細胞を提供する。According to a third aspect of the invention, the present invention provides a host cell transformed with a vector according to the first or second aspect of the invention.
宿主細胞は任意の真核生成細胞たとえば植物または混
入細胞であつてもよいが、哺乳動物細胞、たとえばCHO
細胞もしくは骨髄起源の細胞たとえば骨髄腫細胞または
ハイブリドーマ細胞であることが好ましい。The host cell may be any eukaryotic cell, such as a plant or contaminating cell, but a mammalian cell such as CHO.
It is preferably a cell or a cell of bone marrow origin such as a myeloma cell or a hybridoma cell.
本発明は、その第四の特徴として、本発明の第三の特
徴によるトランスフエクシヨンを受けた細胞の培養によ
つて異種ポリペプチドを製造する方法を提供する。As a fourth feature of the present invention, the present invention provides a method for producing a heterologous polypeptide by culturing cells that have undergone the transformation according to the third feature of the present invention.
本発明は、その第五の特徴として、hCMV-MIE遺伝子の
プロモーター、エンハンサー、および最初のイントロン
を含めた実質的に完全な５′−非翻訳領域からなるDNA
配列の、異種遺伝子の発現のための使用を提供する。As a fifth feature of the present invention, a DNA consisting of a substantially complete 5'-untranslated region including the promoter, enhancer, and first intron of the hCMV-MIE gene.
The use of the sequences for the expression of heterologous genes is provided.
本発明の第五の特徴の好ましい態様においては、hCMV
-MIE誘導DNA配列は、異種遺伝子のDNA暗号配列に直列連
結される。In a preferred embodiment of the fifth aspect of the present invention, hCMV
-The MIE-derived DNA sequence is tandemly linked to the DNA coding sequence of the heterologous gene.
本発明の範囲には、プラスミドpCMGS、pHT.1およびpE
E6hCMVも包含される。Within the scope of the invention are the plasmids pCMGS, pHT.1 and pE.
E6hCMV is also included.
図面の簡単な説明 本発明を添付の図面を参照しながらさらに説明するが、
これは単なる例示である。図中、 第１図は、プラスミドpSVLGS.1を図示的に表示したもの
であり、 第２図は、プラスミドpHT.1を図示的に表示したもので
あり、 第３図は、プラスミドpCMGSを図示的に表示したもので
あり、 第４図は、最初のイントロンおよび修飾翻訳「開始」部
位を含むhCMV-MIEのプロモーター−エンハンサーの完全
配列を示し、 第５図は、プラスミドpEE6、hCMVを図示的に表示したも
のである。BRIEF DESCRIPTION OF THE DRAWINGS The present invention will be further described with reference to the accompanying drawings,
This is just an example. In the figure, FIG. 1 is a schematic representation of the plasmid pSVLGS.1, FIG. 2 is a schematic representation of the plasmid pHT.1, and FIG. 3 is a schematic representation of the plasmid pCMGS. FIG. 4 shows the complete promoter-enhancer sequence of hCMV-MIE, including the first intron and modified translational “start” site, and FIG. 5 illustrates plasmid pEE6, hCMV. It is what was displayed in.
態様の詳細な説明 例１ hCMVのPst-1mフラグメント（ポシヤルトら；セル、第
41巻、第521〜530頁、1985年；スペーテおよびモカルス
キー：ジヤーナル・オブ・ヴアイロロジー、第56巻、第
１号、第135〜143頁、1985年）はMIE遺伝子のプロモー
ター−エンハンサーと、５′非翻訳リーダーの大部分を
最初のイントロンを含めて含有する。５′非翻訳配列の
残りの部分は、約20塩基対の小さな付加配列を結合させ
ることで再生できる。Detailed Description of Embodiments Example 1 Pst-1m fragment of hCMV (Possiart et al .; Cell, No.
41, 521-530, 1985; Spete and Mokarsky: Journal of Virology, 56, No. 1, 135-143, 1985) are promoter-enhancers of the MIE gene and 5 '. Contains most of the untranslated leader, including the first intron. The rest of the 5'untranslated sequence can be regenerated by joining a small additional sequence of about 20 base pairs.
多くの真核生物遺伝子は、翻訳開始部位と重複するNc
o1制限部位（５′−CCATGG−３′）を有し、この配列が
好ましい翻訳開始シグナル５′ACCATGPu3′の部分を形
成することが多い。hCMV-MIE遺伝子はタンパク質暗号配
列の最初にNco1部位をもたないが、単一の塩基対変化
で、「コザク」コンセンサス開シグナルへのより一層の
類似と、Nco1認識部位の導入の両者が、この配列に生じ
る。したがつて、配列 の１対の相補性オリゴヌクレオチドを合成した。これ
は、hCMVのPst-1mフラグメントに融合させると、翻訳開
始コドンに対して位置−１のＧがＣに１個変化したMIE
遺伝子の完全な５′非翻訳配列が再生される。Many eukaryotic genes have Nc that overlaps with the translation initiation site.
Often, it has an o1 restriction site (5'-CCATGG-3 ') and this sequence forms part of the preferred translation initiation signal 5'ACCATGPu3'. The hCMV-MIE gene does not have an Nco1 site at the beginning of the protein coding sequence, but with a single base pair change, both the closer similarity to the "Kozaku" consensus open signal and the introduction of the Nco1 recognition site Occurs in this array. Therefore, the array A pair of complementary oligonucleotides were synthesized. This is because when fused to the Pst-1m fragment of hCMV, a GIE at position -1 was changed to a C to the translation initiation codon.
The complete 5'untranslated sequence of the gene is regenerated.
この合成DNAフラグメントをhCMV-Pst-1mプロモーター
−エンハンサリーダーフラグメントとグルタミンシンテ
ターゼ（GS）暗号配列の間に、Pst-1mフラグメントと合
成オリゴマーのNco1消化pSV2.GSとのリゲーシヨンによ
つて導入し、新しいプラスミド、pCMGSを発生させた（p
SV2.GSの製造は公告国際特許出願第WO 8704462号に記載
されている）。pCMGSは第３図に示す。すなわち、pCMGS
は次の配列にhCMV-MIEプロモーター−エンハンサーの上
流に上記合成オリゴマー（ここでは単に便利なPst1-Nco
1「アダプター」として働く。）、hCMV-MIEプロモータ
ー、および翻訳開始部位で暗号配列に直接融合した、最
初のイントロンを含むMIE遺伝子の完全５′非翻訳領域
から構成されるハイブリツド転写単位を含有する。This synthetic DNA fragment was introduced between the hCMV-Pst-1m promoter-enhancer leader fragment and the glutamine synthetase (GS) coding sequence by ligation of the Pst-1m fragment and the synthetic oligomer Nco1 digested pSV2.GS, A plasmid, pCMGS, was generated (p
The manufacture of SV2.GS is described in published international patent application WO 8704462). pCMGS is shown in FIG. Ie pCMGS
Is the synthetic oligomer above the hCMV-MIE promoter-enhancer (here is simply the convenient Pst1-Nco
1 Work as an "adapter". ), A hCMV-MIE promoter, and a hybrid transcription unit composed of the complete 5'untranslated region of the MIE gene, including the first intron, fused directly to the coding sequence at the translation start site.
pCMGSをリン酸カルシウム仲介トランスフエクシヨン
によつてCHO-KI細胞に導入し、プラスミドをGS-インヒ
ビター、メチオニンスルホキシミン（MSX）に対する抵
抗性の付与能力について試験した。pSV2.GSとの比較結
果を第１表に示す。pCMGS was introduced into CHO-KI cells by a calcium phosphate mediated transfection and the plasmids were tested for their ability to confer resistance to the GS-inhibitor, methionine sulfoximine (MSX). Table 1 shows the results of comparison with pSV2.GS.
pCMGSがpSV2.GSと類似の頻度で20M MSXに対する抵抗
性を付与できることは、このベクターで発生GS酵素が実
際に発現されることを示している。The ability of pCMGS to confer resistance to 20M MSX with a similar frequency as pSV2.GS indicates that the nascent GS enzyme is actually expressed in this vector.
例２ pTIMP 1に用いられたTIMP cDNAとSV40ポリアデニレー
シヨンシグナル（ドチヤテイら：ネイチヤー、第318
巻、第66〜69頁、1985年）をpEE6の唯一のHind IIIおよ
びBam HI部位に挿入してpEE6TIMPを創製した。pEE6は、
哺乳動物細胞内での複製を抑制する配列が除去された細
菌ベクターである。これはpCT54のXmn I〜Bcl I部分
（エムタージユら：プロシーデイングズ・オブ・ザ・ナ
シヨナル・アカデミー・オブ・サイエンシズ・オブ・ザ
・ユナイテツド・ステイツ・オブ・アメリカ、第80巻、
第3671〜3675頁、1983年）をpSP64（メルトンら：ヌク
レイツク・アシツズ・リサーチ、第12巻、第7035頁、19
84年）、Hind IIIおよびEco RI部位の間に挿入されたポ
リリンカーを含有する。Bam HIおよびSal I部位はポリ
リンカーから消化によつて予め除去し、クレノウ酵素で
充填し、再リゲーシヨンした。Bcl I〜Bam HIフラグメ
ントは237bp SV 40前期ポリアデニレーシヨンシグナル
（SV40 2770〜2533）である。Bam HI〜Bgl Iフラグメン
トはpBR328（375〜2422）から誘導され、Sal IとAva I
部位の間（651〜1425）を欠失させ、ついでAva I部位に
Sal Iリンカーを付加したものである。Bgl I部位からXm
n I部位までの配列は64のβ−ラクタマーゼ遺伝子に由
来するhCMVMIEプロモーターーエンハンサーおよび５′
非翻訳配列を含有する2129塩基対のNco1フラグメントを
部分Nco1消化によつてpCMGSから単離し、pEE6.TIMP中の
TIMPの翻訳開始シグナルと重複するNco1部位に挿入し
て、プラスミドpHT.1（第２図に示す）を発生させた。 Example 2 TIMP cDNA used for pTIMP 1 and SV40 polyadenylation signal (Dochiya et al .: Nature, No. 318)
Vol. 66-69, 1985) was inserted into the unique Hind III and Bam HI sites of pEE6 to create pEE6TIMP. pEE6 is
It is a bacterial vector from which a sequence that suppresses replication in mammalian cells has been removed. This is the Xmn I ~ Bcl I part of pCT54 (Emtage Yu et al .: Proceedings of the National Academy of Sciences of the United States of America, Volume 80,
3671-3675, 1983) pSP64 (Melton et al .: Nucleic Assists Research, vol. 12, p. 7035, 19).
1984), containing a polylinker inserted between the Hind III and Eco RI sites. The Bam HI and Sal I sites were previously removed from the polylinker by digestion, filled in with Klenow enzyme and religated. The Bcl I to Bam HI fragment is the 237 bp SV40 early polyadenylation signal (SV40 2770-2533). Bam HI~ Bgl I fragment is derived from pBR328 (375~2422), Sal I and Ava I
Between the sites (651-1425) and then at the Ava I site
Sal I linker added. Xm from Bgl I site
The sequence up to the n I site is derived from 64 β-lactamase genes, the hCMVMIE promoter enhancer and the 5 ′
A 2129 base pair Nco1 fragment containing untranslated sequences was isolated from pCMGS by partial Nco1 digestion and was isolated in pEE6.TIMP.
The plasmid pHT.1 (shown in FIG. 2) was generated by inserting into the Nco1 site overlapping the translation initiation signal of TIMP.
GS遺伝子は、Pvu1消化pSVLGS.1に合成Bam HIリンカー
を付加させたのち、pSVLGS.1の5.5K Pvu1〜BamHIフラグ
メント（第１図）をpHT.1のBamHI部位に導入してpHT.1G
Sを発生させることにより、永久細胞系の選択を可能に
するためにpHT.1に導入された。このプラスミドではhCM
V-TMIEおよびGS転写単位は同じ配列で転写する。For the GS gene, after adding a synthetic Bam HI linker to Pvu1 digested pSVLGS.1, the 5.5K Pvu1 to BamHI fragment of pSVLGS.1 (Fig. 1) was introduced into the BamHI site of pHT.1 to obtain pHT.1G.
By generating S, it was introduced into pHT.1 to allow selection of permanent cell lines. HCM in this plasmid
The V-TMIE and GS transcription units transcribe with the same sequence.
pHT.1GSはリン酸カルシウム仲介トランスフエクシヨ
ンによつてCHO-KI細胞中に導入され、20μM MSXに対し
て抵抗性のクローンをトランスフエクシヨン２〜３週後
に単離した。TIMP分泌速度は、培養上澄液を、捕獲抗体
としてヒツジ抗TIMPポリクローナル抗体、認識抗体とし
てマウスTIMPモノクローナル抗体、モノクローナル抗体
の結合はヒツジ抗マウスIgGペルオキシダーゼ抱合体を
用いて明らかにする特異的２サイトELISAで試験するこ
とによつて測定された。アツセイの検量のための標準と
しては、精製した天然TIMPを用いた。全曲線が２〜200n
g/mlの範囲内で直線であつた。CHO細胞調節培養メジウ
ム中では非特異的反応は検出されなかつた。pHT.1GS was introduced into CHO-KI cells by calcium phosphate mediated transfection, and clones resistant to 20 μM MSX were isolated 2-3 weeks after transfection. The TIMP secretion rate is clarified using a culture supernatant, using a sheep anti-TIMP polyclonal antibody as a capture antibody, a mouse TIMP monoclonal antibody as a recognition antibody, and binding of the monoclonal antibody using a sheep anti-mouse IgG peroxidase conjugate. Determined by testing in ELISA. Purified native TIMP was used as a standard for assay calibration. 2 to 200n for all curves
It was a straight line within the range of g / ml. No non-specific reaction was detected in CHO cell-conditioned medium.
ひとつの細胞系GS.19をついで再びクローニングし
た。サブクローンGS19-12はTIMPを３×108分子／細胞／
日というきわめて高いレベルで分泌する。この細胞系か
ら抽出される総ゲノムDNAを、標準方法を用いてサザン
ブロツト解析によりTIMPプローブとハイブリダイゼーシ
ヨンさせて、各細胞ごとにTIMP転写単位の１個の無傷の
コピーを含有することが明らかにされた（ならびに２個
の再配置プラスミドバンド）。この細胞系を高レベルの
MSXで選択し、最初の選択で500μＭのMSXに抵抗性を示
した細胞のプールを単離し、再クローニングした。クロ
ーンGS-19.6（500）14は３×109分子／細胞／日のTIMP
を分泌する。この細胞系におけるベクターコピー数は約
20〜30コピー／細胞である。一層遺伝子を増幅させるた
めの選択の次回の反復では、TIMP分泌の増大を生じなか
つた。One cell line, GS.19, was then recloned. Subclone GS19-12 has 3 × 10 8 TIMP molecules / cell /
Secreted at an extremely high level of the day. Total genomic DNA extracted from this cell line was hybridized with a TIMP probe by Southern blot analysis using standard methods to reveal that each cell contained one intact copy of the TIMP transcription unit. (As well as two rearranged plasmid bands). High levels of this cell line
Pools of cells selected with MSX and resistant to 500 μM MSX in the first selection were isolated and recloned. Clone GS-19.6 (500) 14 is TIMP with 3 × 10 9 molecules / cell / day
Secrete. The vector copy number in this cell line is approximately
20-30 copies / cell. The next round of selection to further amplify the gene did not result in increased TIMP secretion.
すなわち、pHT.1からのhCMV-TMIE転写転位はCHO-KI細
胞中、細胞あたりほぼ単一のコピーできわめて効率的に
発現されることが可能で、遺伝子増幅１回で現方法を用
いて最大の分泌速度が導かれるようである。In other words, the hCMV-TMIE transposition from pHT.1 can be expressed very efficiently in CHO-KI cells with almost a single copy per cell, and the maximum amount of gene amplification can be achieved using the current method once. It seems that the secretion rate of is induced.
例３ hCMV-MIEプロモーター−エンハーサー−リーダーが他
のタンパク質配列の効率的な発現を企図しても使用でき
るかどうかを試験するために、２種の異なるが類縁のプ
ラスミノーゲンアクテイベータ暗号配列（PA−１および
PA−２と呼ばれる）を、このタンパク質暗号配列が直接
hCMV配列に融合したベクター中、CHO-KI細胞に導入し
た。Example 3 To test whether the hCMV-MIE promoter-enhercer-leader can be used to contemplate the efficient expression of other protein sequences, two different but related plasminogen activator coding sequences ( PA-1 and
This protein coding sequence is directly
It was introduced into CHO-KI cells in a vector fused to the hCMV sequence.
いずれの場合も、翻訳配列の最初にNcol部位がなく、
したがつて、合成オリゴヌクレオチドを使用して翻訳領
域内の適当な制限部位からその標準暗号配列を再生し
た。pHT.1に使用したような修飾hCMV翻訳開始シグナル
の配列も合成オリゴヌクレオチド内に構築し、これをつ
いでPst−１制限部位で終結させた。hCMVのPst−1mフラ
グメントを次にこの部位に挿入し、完全なプロモーター
−エンハンサーリーダー配列を創製した。In each case, there is no Ncol site at the beginning of the translated sequence,
Therefore, synthetic oligonucleotides were used to regenerate the standard coding sequence from appropriate restriction sites within the translation region. The sequence of the modified hCMV translation initiation signal as used in pHT.1 was also constructed in a synthetic oligonucleotide, which was then terminated at the Pst-1 restriction site. The Pst-1m fragment of hCMV was then inserted at this site to create the complete promoter-enhancer leader sequence.
hCMV−プラスミノーゲンアクテイベーター転写部位
は、CHO−KI細胞中に、上述のように唯一のBamHI部位に
GS遺伝子を挿入したのちに挿入し、プラスミノーゲンア
クテイベーターを分泌するMSX抵抗性細胞を単離した。The hCMV-plasminogen activator transcription site is unique to the BamHI site in CHO-KI cells as described above.
MSX-resistant cells, which insert after the GS gene and secrete the plasminogen activator, were isolated.
各場合における最善の初期トランスフエクシヨ細胞系
の分泌速度を第２表に示す。これから、hCMV−プロモー
ター−エンハンサー−リーダーは、これらの２種のプス
ミノーゲンアクテイベータータンパク質の効率的な発現
を企図して同様に使用できることが明らかである。The secretion rate of the best early transfection cell line in each case is shown in Table 2. From this it is clear that the hCMV-promoter-enhancer-leader can be used as well, with the intention of efficient expression of these two psminogen activator proteins.
例４ pEE6hCMVは、hCMVのPst-1mフラグメント、Hind III消
化pEE 6および次の配列： を有する相補性オリゴヌクレオチドをリゲーシヨンさせ
て作成した。 Example 4 pEE6hCMV is a Pst-1m fragment of hCMV, Hind III digested pEE 6 and the following sequence: Was prepared by ligating a complementary oligonucleotide having
免疫グロブリン軽鎖をコードするcDNAを、pEE6.hCMV
のEcoRI部位に、hCMV-MIEプロモーター−エンハンサリ
ー−リーダーがこのcDNAの発現を支配できるようにまた
複数のSV40起点を含有する選択可能なマーカー遺伝子が
各プラスミドのBam HI部位に挿入されるように、挿入し
た。CDNA encoding the immunoglobulin light chain was cloned into pEE6.hCMV
At the EcoRI site of hCMV-MIE promoter-enhancer-leader to control the expression of this cDNA and to insert a selectable marker gene containing multiple SV40 origins into the BamHI site of each plasmid. , Inserted.
このプラスミドを標準DEAE−デキストラントランスフ
エクシヨン法によつてCOS−１サル腎臓細胞にトランス
フエクシヨンし、トランスフエクシヨン72時間後に、短
時間、発現をモニタリングした。軽鎖は少なくとも1000
ng/mlの速度でメジウム中に分泌され、全hCMV-MIE5′−
非翻訳配列を翻訳開始ATGまで（翻訳開始ATGは含まな
い）ついでマウス免疫グロブリン軽鎖遺伝子の天然５′
−非翻訳領域の15塩基を含有する転写部位から、実際に
軽鎖が発現することを示している。This plasmid was transfected into COS-1 monkey kidney cells by the standard DEAE-dextran transfection method, and 72 hours after transfection, expression was monitored briefly. At least 1000 light chains
Secreted in medium at a rate of ng / ml, total hCMV-MIE5'-
Untranslated sequence up to translation initiation ATG (not including translation initiation ATG), followed by the natural 5'of mouse immunoglobulin light chain gene
-It is shown that the light chain is actually expressed from the transcription site containing 15 bases of the untranslated region.
フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｃ１２Ｒ 1:92） (Ｃ１２Ｎ 9/64 (Ｃ１２Ｎ 5/10 Ｃ１２Ｒ 1:91） Ｃ１２Ｒ 1:91） (Ｃ１２Ｐ 21/00 (Ｃ１２Ｎ 9/64 Ｃ１２Ｒ 1:91） Ｃ１２Ｒ 1:91） 7729−4Ｂ Ｃ１２Ｎ 5/00 Ｂ (Ｃ１２Ｐ 21/00 Ｃ１２Ｒ 1:92） Ｃ１２Ｒ 1:91） 1:91） Continuation of front page (51) Int.Cl. 6 Identification code Internal reference number FI Technical display area C12R 1:92) (C12N 9/64 (C12N 5/10 C12R 1:91) C12R 1:91) (C12P 21 / 00 (C12N 9/64 C12R 1:91) C12R 1:91) 7729-4B C12N 5/00 B (C12P 21/00 C12R 1:92) C12R 1:91) 1:91)
Claims (12)
サー、および最初のイントロンを含めて実質的に完全な
５′−非翻訳領域からなるDNA配列を含有するベクタ
ー。1. A vector containing a DNA sequence consisting of a substantially complete 5'-untranslated region including the promoter, enhancer, and first intron of the hCMV-MIE gene.
部位を包含する請求の範囲第１項のベクター。2. The vector according to claim 1, which contains a restriction site for insertion of a heterologous gene.
サー、および最初のイントロンを含めて実質的に完全な
５′−非翻訳領域からなるDNA配列を異種遺伝子の上流
に含有するベクター。3. A vector containing, upstream of a heterologous gene, a DNA sequence consisting of a substantially complete 5'-untranslated region including the promoter, enhancer, and first intron of the hCMV-MIE gene.
に直接連結する請求の範囲第３項のベクター。4. The vector according to claim 3, wherein the hCMV-MIE DNA is directly linked to the DNA coding sequence of a heterologous gene.
る請求の範囲第４項のベクター。5. The vector according to claim 4, wherein the hCMV-MIE DNA contains a translation initiation signal.
暗号配列を有し、更にSV40イントロン及びポリアデニレ
ーション配列を有するプラスミドpCMGSである、請求の
範囲第４項のベクター。6. The vector according to claim 4, which is a plasmid pCMGS having a glutamine synthetase coding sequence as a heterologous gene and further having an SV40 intron and a polyadenylation sequence.
配列を有するプラスミドpEE6.hCMVである、請求の範囲
第４項のベクター。7. The vector according to claim 4, which is a plasmid pEE6.hCMV having an immunoglobulin light chain coding sequence as a heterologous gene.
織インヒビター（TIMP）暗号配列を有するプラスミドpH
T.1である、請求の範囲第４項のベクター。8. A plasmid pH having a tissue inhibitor of metalloproteinase (TIMP) coding sequence as a heterologous gene.
The vector of claim 4 which is T.1.
かのベクターでトランスフェクションされた宿主細胞。9. A host cell transfected with the vector according to any one of claims 1 to 8.
ことによる異種ポリペプチドの製造方法。10. A method for producing a heterologous polypeptide by culturing the host cell according to claim 9.
ンサー、および最初のイントロンを含めて実質的に完全
な５′−非翻訳領域からなるDNA配列を用いて、異種遺
伝子の発現を行う、DNA配列の使用方法。11. A DNA sequence for heterologous gene expression using a DNA sequence consisting of a substantially complete 5'-untranslated region including the promoter, enhancer, and first intron of the hCMV-MIE gene. how to use.
列に直接連結させる請求の範囲第11項のDNA配列の使用
方法。12. The method for using the DNA sequence according to claim 11, wherein the hCMV-MIE-derived DNA is directly linked to the coding sequence of a heterologous gene.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8717430 | 1987-07-23 | ||
| GB878717430A GB8717430D0 (en) | 1987-07-23 | 1987-07-23 | Recombinant dna product |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02500330A JPH02500330A (en) | 1990-02-08 |
| JP2505268B2 true JP2505268B2 (en) | 1996-06-05 |
Family
ID=10621156
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63506088A Expired - Lifetime JP2505268B2 (en) | 1987-07-23 | 1988-07-22 | Recombinant DNA expression vector |
Country Status (7)
| Country | Link |
|---|---|
| US (2) | US5591639A (en) |
| EP (1) | EP0323997B1 (en) |
| JP (1) | JP2505268B2 (en) |
| AT (1) | ATE88501T1 (en) |
| DE (1) | DE3880468T2 (en) |
| GB (1) | GB8717430D0 (en) |
| WO (1) | WO1989001036A1 (en) |
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| US5658759A (en) | 1997-08-19 |
| EP0323997A1 (en) | 1989-07-19 |
| ATE88501T1 (en) | 1993-05-15 |
| GB8717430D0 (en) | 1987-08-26 |
| JPH02500330A (en) | 1990-02-08 |
| US5591639A (en) | 1997-01-07 |
| WO1989001036A1 (en) | 1989-02-09 |
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